Modulation of the physicochemical or pharmacokinetic properties of a drug in vivo may be affected by conjugation of the drug with a carrier. In particular, conjugation of a drug with a carrier is frequently used as a means to increase the therapeutic duration of action, reduce the maximum concentration of the drug after administration or localize delivery of the drug to a desired tissue or compartment or a combination of these purposes. Typically, carriers in drug delivery systems are either (a) used in a non-covalent fashion with the drug physicochemically formulated into a solvent-carrier mixture or (b) linked by covalent attachment of a carrier reagent to a functional group present in the drug.
Non-covalent approaches require a highly efficient drug encapsulation to prevent uncontrolled burst release of the drug that may occur either at initial administration of the carrier-drug system or during degradation of the carrier after administration to a subject. Restraining the diffusion of an unbound, water-soluble drug molecule requires strong van der Waals contacts, frequently mediated through hydrophobic moieties, hydrogen-bonding, or electrostatic binding mediated through charged moieties. Many conformationally sensitive drugs, such as proteins, peptides, or antibodies are rendered dysfunctional during the encapsulation process and/or during subsequent storage of the encapsulated drug.
Alternatively, a drug may be covalently conjugated to a carrier via a stable linker or via a reversible linker moiety from which the drug is released. If the drug is stably connected to the carrier, such a conjugate needs to exhibit sufficient residual activity to have a pharmaceutical effect and the conjugate is constantly in an active form.
If the drug is conjugated to the carrier through a cleavable linker, such conjugates are typically referred to as carrier-linked drugs. This approach can be applied to various classes and sizes of biologically active molecules, from low molecular weight organic molecules, natural products, antibodies and analogs thereof, proteins, peptides, and the like. An important consideration for carrier-linked drugs is the mechanism for releasing the drug from the carrier. The release mechanism may be enzymatic, pH-dependent, or via autonomous hydrolysis. Typically, the drug release is not easily controllable and difficult to sustain over long time periods.
There continues to be a need for new drug delivery systems suitable for the sustained release of biologically active moieties in therapeutic applications. Described herein are drug delivery systems that provide sustained release of biologically active moieties for therapeutically relevant applications.